Left Atrial Appendage Occlusion An Alternative to Anticoagulation - - PowerPoint PPT Presentation

Left Atrial Appendage Occlusion

An Alternative to Anticoagulation

Jonathon Adams, MD, FACC, FHRS

DISCLOSURE

Relevant Financial Relationship(s)

None

Off Label Usage

None

Acknowledgement

Ken Huber, MD, FACC

OBJECTIVES

• Background
• What is left atrial appendage occlusion?
• How do the efficacy and safety of LAAC compare to OAC?
• Who to refer for evaluation?

Atrial Fibrillation → An Epidemic

Savelieva, et al. Clin Cardiol2008;31

5 Million 10 Million

Distribution of AF by Age

Over 50% of AF occurs in the 6% of the population ≥ 75 years of age

WM Feinberg, et al. Arch Int Med 1995;155:469-73

Atrial Fibrillation → Stroke Risk

• AF increases the risk of stroke 5-fold (5-6% annual risk)
• AF is responsible for 15-20% of all strokes

D.R. Holmes. Seminars in Neurology. 2010;30:528 Heart Disease and Stroke Statistical Update: 2009 Circulation, 1-27-09 Stroke 1991;22(18)

0% 10% 20% 30% 40% 50–59 60–69 70–79 80–89 % AF Strokes Age (years)

• 800,000 strokes/yr in U.S. = 100,000 AF strokes/yr

Thrombosis/Embolization

Electrical Fibrillation Insufficient contraction of LAA Stagnant blood flow Thrombosis / clot formation Thromboembolism Stroke

Johnson, EurJ Cardiothoracic Surg 2000;17

LAA – Culprit

Location of Thrombi in Left Atrium

20 40 60 80 100

Stoddard: JACC, '95 Manning: Circ, '94 Aberg: Acta Med Scan, '69 Tsai: JFMA, '90 Klein: Int J Card Imag: '93 Manning: Circ, '94 Klein: Circ, '94 Leung: JACC, '94 Hart: Stroke, '94 Total

Left Atrial Appendage Left Atrium

Blackshear et al., Ann Thoracic Surg, 1996;61:755

Location Frequency (%)

90% in LAA

LAA : Variable Structure

Stroke Prevalence Based Upon Left Atrial Appendage Morphology

5 10 15 20

Chicken Wing Windsock Cactus Cauliflower

OR 0.2 (.04-0.8) OR 1.1 (0.4-3.2) OR 2.5 (1.0-6.1) OR 2.0 (0.2-7.2)

4% 12% 2 4 6 8 10 12 14 Chicken Wing Non-Chicken Wing

Stroke Rate (%) Stroke Rate (%)

Di Biase, L, et al. JACC 2012

ANTICOAGULATION

Eur Heart J 2012;33:2719-2747

Hypertrophic Cardiomyopathy

WHAT ABOUT ASPIRIN?

AVERROES Study

Outcome Apixaban (N=2808) Aspirin (N=2791) Hazard Ratio (95% CI) P Value Stroke or systemic embolism 51 (1.6% per yr) 113 (3.7% per yr) 0.45 (0.32-0.62) <0.001 Hospitalizationfor cardiovascular cause 367 (12.6% per yr) 455 (15.9% per yr) 0.79 (0.69-0.91) <0.001 Major bleeding 44 (1.4% per yr) 39 (1.2% per yr) 1.13 (0.74-1.75) 0.57 Connolly, et al. NEJM 364;9, 2011

Preventing Stroke in Non-Valvular AF

Imputed Benefit of Different Strategies (vs. Control)

Limitations of Anticoagulation

Warfarin

• Bleeding risk
• Daily regimen
• Noncompliance
• INR monitoring
• Drug interactions

DOAC

• Bleeding risk
• Daily or BID regimen
• Noncompliance
• High cost
• Lack of reversal agents
• Except Dabigatran

Major Bleeding

Treatment Drug D/C Rate Major Bleeding

Warfarin 17-28% 3.1-3.6% Dabigatran(150 mg) 21% 3.3% Rivaroxaban(20 mg) 24% 3.6% Apixaban(5 mg) 25% 2.1% Edoxaban (60 mg) 33% 2.8%

1Connolly, S. NEJM 2009; 361:1139-1151 – 2 yrs follow-up (Corrected) 2Patel, M. NEJM 2011; 365:883-891 – 1.9 yrs follow-up, ITT 3Granger, C NEJM 2011; 365:981-992 – 1.8 yrs follow-up, 4Giugliano, R. NEJM 2013; 369(22): 2093-2104 – 2.8 yrs follow-up.

NVAF: Odds of Intracranial Hemorrhage & Age in 145 Case-patients (INR 2.0-3.0) and 870 Controls

MC Fang et al. Ann Int Med 2004;141:745

1 2 3 4 5 < 60 60-64 65-69 70-74 75-79 80-84 ≥85

Intracerebral (> INR) Subdural (> Trauma) Age (yrs) Relative Odds

Significant Undertreatment

44.3% 58.1% 60.7% 57.3% 35.4% 0% 10% 20% 30% 40% 50% 60% 70% < 55 55-64 65-74 75-84 85+

% Use of Warfarin

Age (years)

• Especially those at high risk

40 to 50% not treated

• Levy S, Circulation1999 • Baker WL, J Man Care Pharm2009
• Samsa, Arch Int Med 2000 • Reynolds MR, Am J Cardiol2006

Low Warfarin Use in High-risk Patients

• Medicare claims

data, 2006-2007 – 27,174 patients – Warfarin use less than 60%

• Piccini. Heart Rhythm 2012

0% 20% 40% 60% 80% 100% 1 2 3 4 5 6 CHADS2 Score

Warfarin Use by CHADS2 Score

p<0.001

Bleeding Risk Assessment

Lip GY, JACC 2011 Apostolakis et al. JACC 2013;Dec 12

ATRIA / HEMORR2HAGES / HAS-BLED

HAS-BLED

• Similar predictors for stroke and bleed
• Primarily identifies patients at risk for extracranial bleeding

Letter Clinical Characteristic Points Awarded H Hypertension 1 A Abnormal renal and liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding 1 L Labile INRs 1 E Elderly (e.g., age > 65 years) 1 D Drugs or Alcohol (1 point each) 1 or 2 Maximum 9 points

Net Benefit: Risk / Reward

• Balance difficult → specific patient

CHA2DS2VASC 1 2 3 4 5 % Stroke 1.3 2.2 3.2 4.0 6.7 % Bleed 0.9 3.4 4.1 5.8 8.9 9.1 HAS-BLED 1 2 3 4 5 ? ? ?

Mod High Low High Mod Low

Fundamental Treatment Dilemma

Atrial Fibrillation – Stroke

Non-pharmacologic Treatment

Non-Pharmacologic Options

WATCHMAN LAAC Device

• FDA approved alternative to anticoagulation for stroke risk

reduction in non-valvular AF

• Only device with long-term data from RCTs and multicenter

registries

• Noninferior to warfarin for stroke risk reduction in nonvalvular

AF

• Statistically superior to warfarin for hemorrhagic stroke,

disabling stroke, and cardiovascular death over long-term follow-up

• 1. Reddy, V et al. JAMA 2014; Vol. 312, No. 19.
• 2. Reddy, V et al. Watchman I: First Report of the 5-Year PROTECT-AF and Extended

PREVAIL Results. TCT 2014.

WATCHMANTMDevice

Minimally Invasive, Local Solution

• Available sizes: 21, 24, 27, 30, 33 mm diameter

Intra-LAA design

• Avoids contact with left atrial wall to help prevent

complications

Nitinol Frame

• Conforms to unique anatomy of the LAA to reduce

embolization risk

• 10 active fixation anchors - designed to engage

tissue for stability

Proximal Face

• Minimizes surface area facing the left atrium to

reduce post-implant thrombus formation

• 160 micron membrane PET cap designed to block

emboli and promote healing

Warfarin Cessation

• 92% after 45 days, >99% after 12 months1
• 95% implant success rate1

Anchors 160 Micron Membrane

Who is Eligible?

The WATCHMAN™ Device is indicated to reduce the risk of thromboembolism from the LAA in patients with non-valvular atrial fibrillation who:

• Are at increased risk for stroke and systemic embolism based on

CHADS2 or CHA2DS2-VASc scores and are recommended for anticoagulation therapy

• Are deemed by their physicians to be suitable for short-term

warfarin

• Have an appropriate rationale to seek a non-pharmacologic

alternative to warfarin, taking into account the safety and effectiveness of the device compared to warfarin.

Who is Eligible?

• Non-valvular atrial fibrillation
• i.e. NOT due to mitral stenosis or prior mitral valve surgery
• Stroke risk
• CHADS2 ≥ 2
• CHADS2VASc ≥ 3
• Reason to seek non-pharmacologic alternative
• Bleeding
• Falls
• Intolerant of anticoagulation
• Compliance issues
• Ability to tolerate short-term warfarin (~6 weeks)

Implantation Procedure

• One-time implant that does not need to be replaced
• Performed in a cardiac cath lab/EP suite, or hybrid OR
• Performed by a Watchman Team (EP, IC, Imaging, Anesthesia)
• Catheter advanced to the LAA via the femoral vein

(Does not require open heart surgery)

• General anesthesia*
• 1 hour procedure*
• 1-2 day hospital stay*

* Typical to patient treatment in U.S. clinical trials

WATCHMANTM Device

Device Endothelialization

Canine Model – 30 Day Canine Model – 45 Day Human Pathology - 9 Months Post-implant (Non-device related death)

Post-Implant Management

Implant TEE 45 Days 6 Months (from implant Indefinite Warfarin + ASA 81 ASA 325 + Clopidogrel ASA 325

Warfarin Cessation

p = 0.04

Study 45-day 12-month

PROTECT AF 87% >93% CAP 96% >96% PREVAIL 92% >99%

Implant success defined as deployment and release of the device into the left atrial appendage

Warfarin Cessation

PREVAIL Implant Success

No difference between new and experienced operators

Experienced Operators

• n=26
• 96%

New Operators

• n=24
• 93%

p = 0.28

PROTECT AF

5-Year Results

Event Rate (per 100 Pt-Yrs) Rate Ratio (95% CrI) Posterior Probability WATCHMAN Warfarin Non-inferiority Superiority Primary efficacy 2.2 3.7 0.61 (0.42, 1.07) >99.9% 95.4% Stroke (all) 1.5 2.2 0.68 (0.42, 1.37) 99.9% 83% Systemic embolism 0.2 0.0 N/A

• Death

(CV/unexplained) 1.0 2.3 0.44 (0.26, 0.90) >99.9% 98.9%

Source: FDA Oct 2014 Panel Sponsor Presentation.

Meta-Analysis

HR p-value

Efficacy 0.79 0.22 All stroke or SE 1.02 0.94

Ischemic stroke or SE

1.95 0.05

Hemorrhagic stroke

0.22 0.004

Ischemic stroke or SE >7 days

1.56 0.21 CV/unexplained death 0.48 0.006 All-cause death 0.73 0.07 Major bleed, all 1.00 0.98 Major bleeding, nonprocedure-related 0.51 0.002 Series1, 0.785, 8.8 Series1, 1.02, 7.8 Series1, 1.951, 6.8 Series1, 0.216, 6.1 Series1, 1.556, 5.2 Series1, 0.478, 4.3 Series1, 0.734, 3 Series1, 0.995, 2.2 Series1, 0.508, 1.2 Favors WATCHMAN   Favors warfarin Hazard Ratio (95% CI)

Source: Holmes DR, et al. Holmes, DR et al. JACC 2015; In Press. Combined data set of all PROTECT AF and PREVAIL WATCHMAN patients versus chronic warfarin patients

1 0.1 0.01 10

PROTECT AF: 5 Year Mortality WATCHMAN vs. Warfarin

• V. Reddy, H. Sievert, J. Halperin et al. JAMA 2014;312:1988

RRR 60% RRR 34%

Preventing Stroke in Non-Valvular AF

Imputed Benefit of Different Strategies (vs. Control)

Complications – All Studies

Reddy VR, J. Am. Coll Cardiol. 2017;69(3)

SUMMARY

• AF is common & associated with increased risk of stroke
• Anticoagulation is the standard first line therapy for stroke risk

reduction in patients with risk factors

• Not all patients tolerate systemic anticoagulation
• Left atrial appendage occlusion offers a safe and effective

therapy for stroke risk reduction in these patients

Who to Refer?

• Patients with non-valvular AF who have:
• Risk factors for stroke
• Concerns about safety of long-term anticoagulation